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The strains of E. coli are part of a new class of biological
“adjuvants”—substances added to vaccines to boost the human immune
response—that are poised to transform vaccine design, researchers say.

“For 70 years the only adjuvants being used were aluminum salts,”
says Stephen Trent, associate professor of biology at the University of
Texas at Austin. “They worked, but we didn’t fully understand why, and
there were limitations. Then four years ago the first biological
adjuvant was approved by the Food and Drug Administration. I think what
we’re doing is a step forward from that. It’s going to allow us to
design vaccines in a much more intentional way.”

Adjuvants were discovered in the early years of commercial vaccine
production, when it was noticed that batches of vaccine that were
accidentally contaminated often seemed to be more effective than those
that were pure.

“They’re called the ‘dirty little secret’ of immunology,” Trent says.
“If the vials were dirty, they elicited a better immune response.”

What researchers eventually realized was that they could produce a
one-two punch by intentionally adding their own dirt (adjuvant) to the
mix. The main ingredient of the vaccine, which was a killed or
inactivated version of the bacteria or virus that the vaccine was meant
to protect against, did what it was supposed to do. It “taught” the
body’s immune system to recognize it and produce antibodies in response
to it.

The adjuvant amplifies that response by triggering a more general
alarm, which puts more agents of the immune system in circulation in the
bloodstream, where they can then learn to recognize the key antigen.
The result is an immune system more heavily armed to fight the virus or
bacteria when it encounters it in the future.

For about 70 years the adjuvant of choice, in nearly every vaccine
worldwide, was an aluminum salt. Then in 2009, the FDA approved a new
vaccine for human papillomavirus (HPV). It included a new kind of
adjuvant that’s a modified version of an endotoxin molecule.

These molecules, which can be dangerous, appear on the cell surface
of a wide range of bacteria. As a result, humans have evolved over
millions of years to detect and respond to them quickly. They trigger an
immediate red alert.

“In some of its forms an endotoxin can kill you,” Trent says. “But
the adjuvant, which is called MPL, is a very small, carefully modified
piece of it, so it’s able to trigger the immune response without
overdoing it.”

What Trent and his colleagues have done is expand on that basic premise, according to the study published in Proceedings of the National Academy of Sciences.Rather than just work with an inert piece of endotoxin, they’ve engineered E. coli bacteria to express the endotoxin in many configurations on the cell surface.

“These 61 E. coli strains each have a different profile on
their surface,” says Brittany Needham, a doctoral student in Trent’s lab
and the first author on the paper. “In every case the surface structure
of the endotoxin is safe, but it will interact with the immune system
in a range of ways. Suddenly we have a huge potential menu of adjuvants
to test out with different kinds of vaccines.”

One form might work better with cholera vaccine, another with
pertussis (whooping cough), and another with a future HIV vaccine.
Trent, Needham, and their colleagues should be able to fine-tune the
adjuvants with increasing precision as more E. coli strains are engineered and tested, and as their understanding of how they interact with the immune system deepens.

“I think we’re at the dawn of a new age of vaccine design,” Trent
says. “For a long time vaccinology was really a trial-and-error field.
It was a black box. We knew certain things worked. We knew certain
vaccines had certain side effects. But we didn’t entirely know why. Now
that’s changing.”

An additional advantage of their system is that the E. coli
can be engineered to express key viral and bacterial antigens along with
the endotoxin. A single cell could deliver both parts of the one-two
punch, or even a one-two-three punch, if antigens from multiple diseases
were expressed in a single E. coli.”It makes possible a vaccine that provides protection from multiple pathogens at the same time,” Trent says.

The researchers are working on a second round of designer E. coli.
They have also filed a provisional patent on their system and are
working with the university to find a corporate partner to pay for
clinical trials.

“This is ready to go,” Trent says “I can’t predict whether it will
actually make it to the market. But it’s very similar to the adjuvant
that has already been approved, and my instinct is that if a company
will undertake to do the trials, it will get approved. A company could
call us tomorrow, we could send them a strain, and they could start
working.”

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